Fludarabine

WARNING Fludarabine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Fludarabine can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, fludarabine was associated with severe neurologic effects, including blindness, coma, and death. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m 2 /day for 5 to 7 days) than the recommended dose. Similar severe central nervous system toxicity has been rarely (0.2%) reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia. Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine. Patients undergoing treatment with fludarabine should be evaluated and closely monitored for hemolysis. In a clinical investigation using fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended.

WARNINGS: (See boxed warning) There are clear dose-dependent toxic effects seen with fludarabine. Dose levels approximately 4 times greater (96 mg/m 2 /day for 5 to 7 days) than that recommended for CLL (25 mg/m 2 /day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients (36%) who received fludarabine at high doses (96 mg/m 2 /day for 5 to 7 days) developed this severe neurotoxicity. This syndrome has been reported rarely in patients treated with doses in the range of the recommended CLL dose of 25 mg/m 2 /day for 5 days every 28 days. The effect of chronic administration of fludarabine on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy. Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine. In a Phase I study in solid tumor patients, the median time to nadir counts was 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy induced myelosuppression is often reversible, administration of fludarabine requires careful hematologic monitoring. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients. Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs’ test and who may or may not be in remission from their disease. Steroids may or may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with fludarabine developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with fludarabine should be evaluated and closely monitored for hemolysis. Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of non-irradiated blood in fludarabine treated patients. Consideration should, therefore, be given to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with fludarabine. In a clinical investigation using fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended. Of the 133 CLL adult patients in the two trials, there were 29 fatalities during study. Approximately 50% of the fatalities were due to infection and 25% due to progressive disease. Pregnancy Category D Fludarabine may cause fetal harm when administered to a pregnant woman. Fludarabine phosphate was teratogenic in rats and in rabbits. Fludarabine phosphate was administered intravenously at doses of 0, 1, 10 or 30 mg/kg/day to pregnant rats on days 6 to 15 of gestation. At 10 and 30 mg/kg/day in rats, there was an increased incidence of various skeletal malformations. Fludarabine phosphate was administered intravenously at doses of 0, 1, 5 or 8 mg/kg/day to pregnant rabbits on days 6 to 15 of gestation. Dose-related teratogenic effects manifested by external deformities and skeletal malformations were observed in the rabbits at 5 and 8 mg/kg/day. Drug-related deaths or toxic effects on maternal and fetal weights were not observed. There are no adequate and well-controlled studies in pregnant women. If fludarabine is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Pregnancy Category D Fludarabine may cause fetal harm when administered to a pregnant woman. Fludarabine phosphate was teratogenic in rats and in rabbits. Fludarabine phosphate was administered intravenously at doses of 0, 1, 10 or 30 mg/kg/day to pregnant rats on days 6 to 15 of gestation. At 10 and 30 mg/kg/day in rats, there was an increased incidence of various skeletal malformations. Fludarabine phosphate was administered intravenously at doses of 0, 1, 5 or 8 mg/kg/day to pregnant rabbits on days 6 to 15 of gestation. Dose-related teratogenic effects manifested by external deformities and skeletal malformations were observed in the rabbits at 5 and 8 mg/kg/day. Drug-related deaths or toxic effects on maternal and fetal weights were not observed. There are no adequate and well-controlled studies in pregnant women. If fludarabine is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

ADVERSE REACTIONS The most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in CLL patients treated with fludarabine. The most frequently reported adverse events and those reactions which are more clearly related to the drug are arranged below according to body system. Hematopoietic Systems Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with fludarabine. During fludarabine treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm 3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with fludarabine. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in postmarketing surveillance. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients. Life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur in patients receiving fludarabine (see WARNINGS ). The majority of patients rechallenged with fludarabine developed a recurrence in the hemolytic process. Metabolic Tumor lysis syndrome has been reported in CLL patients treated with fludarabine. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria. Nervous System (See WARNINGS ). Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in CLL patients treated with fludarabine at the recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine and one case of wrist-drop was reported. Pulmonary System Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16% and 22% of those treated with fludarabine in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to fludarabine characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed. In postmarketing experience, cases of severe pulmonary toxicity have been observed with fludarabine use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure. After an infectious origin has been excluded, some patients experienced symptom improvement with corticosteroids. Gastrointestinal System Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis, and gastrointestinal bleeding have been reported in patients treated with fludarabine. Cardiovascular Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine. No other severe cardiovascular events were considered to be drug related. Genitourinary System Rare cases of hemorrhagic cystitis have been reported in patients treated with fludarabine. Skin Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with fludarabine. Data in the following table are derived from the 133 patients with CLL who received fludarabine in the MDAH and SWOG studies. PERCENT OF CLL PATIENTS REPORTING NON-HEMATOLOGIC ADVERSE EVENTS ADVERSE EVENTS MDAH (N=101) SWOG (N=32) ANY ADVERSE EVENT 88% 91% BODY AS A WHOLE 72 84 FEVER 60 69 CHILLS 11 19 FATIGUE 10 38 INFECTION 33 44 PAIN 20 22 MALAISE 8 6 DIAPHORESIS 1 13 ALOPECIA 0 3 ANAPHYLAXIS 1 0 HEMORRHAGE 1 0 HYPERGLYCEMIA 1 6 DEHYDRATION 1 0 NEUROLOGICAL 21 69 WEAKNESS 9 65 PARESTHESIA 4 12 HEADACHE 3 0 VISUAL DISTURBANCE 3 15 HEARING LOSS 2 6 SLEEP DISORDER 1 3 DEPRESSION 1 0 CEREBELLAR SYNDROME 1 0 IMPAIRED MENTATION 1 0 PULMONARY 35 69 COUGH 10 44 PNEUMONIA 16 22 DYSPNEA 9 22 SINUSITIS 5 0 PHARYNGITIS 0 9 UPPER RESPIRATORY INFECTION 2 16 ALLERGIC PNEUMONITIS 0 6 EPISTAXIS 1 0 HEMOPTYSIS 1 6 BRONCHITIS 1 0 HYPOXIA 1 0 GASTROINTESTINAL 46 63 NAUSEA/VOMITING 36 31 DIARRHEA 15 13 ANOREXIA 7 34 STOMATITIS 9 0 GI BLEEDING 3 13 ESOPHAGITIS 3 0 MUCOSITIS 2 0 LIVER FAILURE 1 0 ABNORMAL LIVER FUNCTION TEST 1 3 CHOLELITHIASIS 0 3 CONSTIPATION 1 3 DYSPHAGIA 1 0 CUTANEOUS 17 18 RASH 15 15 PRURITUS 1 3 SEBORRHEA 1 0 GENITOURINARY 12 22 DYSURIA 4 3 URINARY INFECTION 2 15 HEMATURIA 2 3 RENAL FAILURE 1 0 ABNORMAL RENAL FUNCTION TEST 1 0 PROTEINURIA 1 0 HESITANCY 0 3 CARDIOVASCULAR 12 38 EDEMA 8 19 ANGINA 0 6 CONGESTIVE HEART FAILURE 0 3 ARRHYTHMIA 0 3 SUPRAVENTRICULAR TACHYCARDIA 0 3 MYOCARDIAL INFARCTION 0 3 DEEP VENOUS THROMBOSIS 1 3 PHLEBITIS 1 3 TRANSIENT ISCHEMIC ATTACK 1 0 ANEURYSM 1 0 CEREBROVASCULAR ACCIDENT 0 3 MUSCULOSKELETAL 7 16 MYALGIA 4 16 OSTEOPOROSIS 2 0 ARTHRALGIA 1 0 TUMOR LYSIS SYNDROME 1 0 More than 3,000 adult patients received fludarabine in studies of other leukemias, lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was consistent with the data presented above.

Hematopoietic Systems Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with fludarabine. During fludarabine treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm 3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with fludarabine. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in postmarketing surveillance. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients. Life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur in patients receiving fludarabine (see WARNINGS ). The majority of patients rechallenged with fludarabine developed a recurrence in the hemolytic process.

Metabolic Tumor lysis syndrome has been reported in CLL patients treated with fludarabine. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria.

Nervous System (See WARNINGS ). Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in CLL patients treated with fludarabine at the recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine and one case of wrist-drop was reported.